Iridium-Catalysed C-H Borylation of Heteroarenes: Balancing Steric and Electronic Regiocontrol

Abstract

The iridium-catalysed borylation of aromatic C-H bonds has become the preferred method for the synthesis of aromatic organoboron compounds. The reaction is highly efficient, tolerant of a broad range of substituents and can be applied to both carbocyclic and heterocyclic substrates. The regioselectivity of C-H activation is dominated by steric considerations and there have been considerable efforts to develop more selective processes for less constrained substrates. However, most of these have focused on benzenoid-type substrates and in contrast, heteroarenes remain much desired but more challenging substrates with the position and/or nature of the heteroatom(s) significantly affecting reactivity and regioselectivity. This review will survey the borylation of heteroarenes, focusing on the influence of steric and electronic effects on regiochemical outcome and, by linking to current mechanistic understandings, will provide insights to what is currently possible and where further developments are required.

Keywords: borylation; catalysis; heteroarenes; iridium; regioselectivity.

Figure 1

Applications of organoboron compounds. MIDA=N‐methyliminodiacetic acid.

Figure 2

Selected classes of organoboron compounds.

Scheme 1

Selected syntheses of aryl organoboron compounds; literature references given in square brackets. dppf=1,1′‐bis(diphenylphosphino)ferrocene, pin=pinacolyl, TMEDA=tetramethylethylenediamine.

Scheme 2

Selected examples of electrophilic aromatic C−H borylation mediated by a) a borenium cation, b) frustrated Lewis pair catalysis, c) BI₃.

Scheme 3

Seminal reports of Ir‐catalysed C−H borylation. bpy=2,2′‐bipyridine, cod=1,5‐cyclooctadiene, dmpe=1,2‐bis(dimethylphosphino)ethane, Ind=indenyl.

Scheme 4

Catalytic cycles of the Ir‐catalysed C−H borylation depicting catalyst regeneration using B₂pin₂ (blue) and HBpin (red). coe=cyclooctene.

Figure 3

Directed C−H borylation. a) Inner‐sphere, b) relay, and c) outer‐sphere mechanisms.

Scheme 5

Ir‐catalyzed C−H borylation of arenes. mtbe=methyl tert‐butyl ether (IUPAC: 2‐methoxy‐2‐methylpropane).

Scheme 6

Directed ortho borylation by a) inner‐sphere control using Silica‐SMAP, b) relay inner‐sphere borylation, c) outer‐sphere mediated coordination.

Scheme 7

Reagent‐based regiocontrolled C−H borylation.

Scheme 8

C−H borylation of 2‐phenylpyridine.

Scheme 9

C‐2 selective C−H borylation of pyrrole, thiophene, and furan using a) excess heterocycle (* C‐3‐borylated furan also observed), b) stoichiometric heterocycle, c) room temperature.

Scheme 10

C−H borylation of substituted pyrroles, thiophenes, and furans. dba=dibenzylideneacetone, Q‐phos=1′‐[bis(1,1‐dimethylethyl)phosphino]‐1,2,3,4,5‐pentaphenylferrocene.

Scheme 11

C−H borylation of substituted thiophenes.

Scheme 12

C−H borylation of N‐substituted pyrroles. S‐Phos=2‐dicyclohexylphosphino‐2′,6′‐dimethoxybiphenyl, TIPS=triisopropylsilyl.

Scheme 13

Directed C−H borylation of five‐membered heterocycles. Cy=cyclohexyl.

Scheme 14

Borylation of porphyrins and corroles.

Scheme 15

C−H borylation of indoles. IMes=1,3‐bis(2,4,6‐trimethylphenyl)imidazolium.

Scheme 16

C−H borylation of benzofused heterocycles.

Scheme 17

ortho‐ and peri‐directed borylation of benzofused heterocycles.

Scheme 18

Inner‐sphere directed borylation of indoles.

Scheme 19

C−H borylation of indazoline derivatives. DMAc=dimethylacetamide.

Scheme 20

Ir‐catalysed C−H borylation of pyridine.

Scheme 21

C−H borylation of 2‐substituted pyridines. TMS=trimethylsilyl.

Scheme 22

C−H borylation of substituted pyridines.

Scheme 23

Borylation of 2,2‐bipyridines.

Scheme 24

Outer‐sphere directed C−H borylation of pyridines.

Scheme 25

Ligand‐mediated outer‐sphere directed C−H borylation of pyridines. OTf⁻=triflate.

Scheme 26

Inner‐sphere directed C−H borylation of 2‐substituted pyridines.

Scheme 27

Ir‐catalysed C−H borylation of quinolines. NIS=N‐iodosuccinimide.

Scheme 28

Directed borylation of quinolines.

Scheme 29

Borylation of imidazole derivatives.

Scheme 30

Borylation of pyrazole and its derivatives.

Scheme 31

Borylation of oxazole derivatives.

Scheme 32

C−H borylation of indazoles. Ms=methanesulfonyl.

Scheme 33

Multidirectional functionalisations of 2H‐indazoles. SEM=2‐(trimethylsilyl)ethoxymethyl.

Scheme 34

C−H borylation of benzoxazole, benzothiazole, and benzimidazole derivatives.

Scheme 35

C−H borylation of diazines.

Scheme 36

C−H borylation of boron‐containing heteroarenes.

Scheme 37

C−H borylation of imidazo‐, pyrazolo‐ and tetrazolopyridine. Amphos=bis(di‐tert‐butyl(4‐dimethylaminophenyl)phosphine, DME=dimethyl ether, XPhos=2‐dicyclohexylphosphino‐2′,4′,6′‐triisopropylbiphenyl.

Scheme 38

C−H borylation of fused heterocycles. μW=microwaves.